This is a first and comprehensive dosimetric planning study to explore the feasibility and potential dosimetric and clinical benefits in the management of patients with left-sided breast cancer receiving whole breast irradiation. This study also analyzed plan robustness in the presence of setup and range errors in addition to the breathing-induced interplay effect. Our results indicate that the SPArc technique with additional degree of freedom in optimization and delivery could not only improve dosimetric quality but also improve plan robustness compared to conventional vIMPT. Recently, there is a trend to use more fields in the breast cancer treatment which might be able to improve the treatment plan quality as well. To provide a more comprehensive comparison among these planning strategies, additional data were included in the supplemental document including the comparison with 3F-IMPT and 5F-IMPT. The result showed that as more beam angles were used in IMPT, the more robust the plan quality is. However, as a tradeoff, multi-field IMPT takes longer to deliver.
In addition to the plan quality improvement, one of the driven motivation of SPArc is to shorten the treatment delivery time and simplify the clinical workflow. The results from this study agree with previous findings that SPArc could shorten the total treatment delivery time based on the modern proton therapy machines where the average of ELST is less than 0.5s [25-28, 40]. In the presence of the large target size, which requires multi-isoenter field matching, SPArc technique could utilize a single-isoenter to simplify the clinical treatment workflow. This is due to the current en face beam angle selection. A 2-iso setup was needed where the target exceeds the lateral maximum field size. e.g. for IBA ProteusONE, the lateral max field size is 20cm. Any target which was larger than 20cm laterally from Beam-Eye-View, requires additional iso. By taking advantage of the arc trajectory, SPArc can deliver the proton spot to the boundary of the lateral region through a tangent beam direction. Thus, SPArc effectively increased the lateral target coverage by using the single iso. Such principle also applies for multi-field IMPT e.g. 3F-IMPT and 5F-IMPT where single-iso setup was needed. However, please be aware of that SPArc or multi-field IMPT will not solve the problem where the target exceed the max field size in superior-inferior direction. In these scenarios, multi-iso setups for SPArc are still needed. For example, three out of eight cases included in this study required a second isocenter. As a result, therapists need to apply an isocenter shift, image validation, and second treatment field in the vIMPT treatment. A review of treatment logs of these three cases found that it took 5.11±0.05 min on average to perform these additional procedures for the 2nd isocenter shift. These additional couch isocenter shift and image acquisition times prolong the overall treatment time and also increase the chance of intrafraction motion [41-43]. Thus, SPArc has the potential to provide a more efficient clinical treatment workflow through one arc trajectory and further reduce the uncertainties from the intrafraction motion.
Cardiac toxicity remains a leading treatment related cause of morbidity and mortality among long-term breast cancer survivors after radiotherapy, especially in the patient population with left-sided breast cancer . Previous studies have found several heart dosimetric metrics related to acute or late cardiotoxicity, although there are still debates in which dosimetric metric and substructures are more related to the acute or late cardiotoxicity [45-48].
Darby et al. found that the rate of the incidence of ischemic heart disease increased linearly with the mean heart dose by 7.4% per Gy . In addition, the RADCOMP (Radiotherapy Comparative Effectiveness) trial has also pointed out that the mean heart dose as a critical indicator for cardiotoxicity [45, 49]. The mean heart dose of the delivered vIMPT plans in our study was 6.38cGy, which is higher than SPArc 4.5cGy (p=0.04). Moreover, there is increasing evidence that the dose of heart substructures needs to be considered. Some studies have focused on the LAD as important parts of the heart associated with radiation-induced heart disease [11, 50]. Conventional proton beam therapy (IMPT or Passive-scattering) could reduce the dose of the heart and LAD in left-side breast cancer patients compared to the photon radiotherapy technique in the high cardiac doses sparing [10, 15, 51]. This study found that the new proton treatment technique, SPArc, could further reduce the D1 of heart and LAD which might mitigate the probability of heart acute and late toxicities. We recognize that the relevance of photon NTCP models to proton therapy has not been established and further proton study would be needed to correlate the proton dose with the cardiotoxicity. The study also found that the contralateral breast mean doses were slightly higher in SPArc planning group compared with vIMPT. It is important to consider and choose the optimal treatment technology for an individual patient considering the possible clinical benefits as well as the limitation of using SPArc technique.
Another critical OAR that could benefit from SPArc is the healthy lung tissue. Reducing the radiation dose to the lung can result in reducing the risk of radiation pneumonitis in patients. Our feasibility study finds that the technology of SPArc can substantially improve not only the heart and LAD sparing but also the lung sparing in comparison with vIMPT. Previous studies have confirmed that proton therapy can significantly reduce the V500(cGy) and V2000(cGy) of the ipsilateral lung by nearly 50% compared to traditional 3DCRT and IMRT [10, 52, 53]. This study found that SPArc plans further reduced all dose-volume parameters while providing a reduced or similarly high-dose radiation volume with IMPT in left-sided WBRT.
The study showed a very interesting result where SPArc has better capability of mitigating the motion interplay effect over IMPT, even though SPArc deliver spots through some tangent arc trajectories which are supposed to be more sensitive to the motion and it has a similar treatment delivery time compared to the single field IMPT. Although the exact rationale behind this phenomenon of interplay effect mitigation is not well understood yet, a similar finding was also reported in the lung mobile target treatment in comparison between SPArc and IMPT . There might have one hypothesis to explain the phenomena. When the number of beam angles increases, it could effectively reduce the dosimetric impact from the proton range uncertainties. For example, when the tumor moves in and out the beamline due to the breathing induce motion, there might have 50% of dose overshooting or undershooting the target from each beam angles using a two-field IMPT plan. On the other hand, SPArc, as an advanced IMPT technique consists of hundreds of beam angles. As a result, overshooting or undershooting the target might only contribute a few percentages of total dose difference in each beam angle. Such advantage may help SPArc effectively mitigate the dosimetric impact from the interplay effect. Because the breathing-induced motion is not significant (< 2mm, supplemental document table s4.) in most of the breast cancer patient population, it is limitation of this motion evaluation study. To prove this new hypothesis of interplay mitigation effect in a relationship to the degree of freedom or beam angles, a more quantitative study would be needed.
Besides, spot characteristics also play an important role in the interplay effect evaluation . In addition, the spot spacing parameter for planning optimization determine the number of the spots where a higher value increases the inter-spot distance and less spot would be used in a plan. Thus, the plan might be more sensitive to the motion uncertainties [55-56]. Similarly, the energy layer spacing parameter determine the number of energy layers . These planning optimization parameters may also play a critical role in the interplay effect. We would recommend different institutions to evaluate the interplay effect based on their own proton beam model and planning optimization parameters in order to offer an optimal treatment plan with an efficiency delivery and robust plan quality .